US11192924B2 - Process for making arylomycin ring analogs - Google Patents

Process for making arylomycin ring analogs Download PDF

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US11192924B2
US11192924B2 US16/581,116 US201916581116A US11192924B2 US 11192924 B2 US11192924 B2 US 11192924B2 US 201916581116 A US201916581116 A US 201916581116A US 11192924 B2 US11192924 B2 US 11192924B2
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alkyl
compound
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salt
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US20200255476A1 (en
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Filip PETRONIJEVIC
Ngiap-Kie Lim
Nicholas Wong
Allen Hong
Haiyun HOU
Xin Linghu
Francis Gosselin
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Genentech Inc
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Genentech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links

Definitions

  • Arylomycin-like compounds have been identified as inhibitors of bacterial signal peptidases and show potential for treatment of infection involving gram-positive and gram-negative bacterials strains that are resistant to existing antibiotics. Synthesis of new arylomycin analogs and in particular preparation of the ring portion of arylomycin, is difficult however. There is accordingly a need for new synthetic procedures for arylomycin analogs and the ring portion thereof.
  • the disclosure provides methods for making the arylomycin ring and variants thereof, and for making arylomycin analogs from the ring.
  • Y is halogen
  • R is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence, or two R groups may form a C 2-6 alkylene that, together with the atoms to which they are attached, may form a five- or six-membered ring;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; cyano-C 1-6 alkyl; or nitro, wherein the amino and hydroxyl moieties may optionally include a protecting group;
  • R 7 is: hydrogen; or C 1-4 alkyl
  • R 8 is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; or cyano-C 1-6 alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group;
  • Pg 1 is an optional amine protecting group
  • Pg 2 is an optional hydroxyl protecting group
  • the subject methods provide unexpectedly better overall yield in producing the ring compound n as well as improved chiral purity via avoidance of potential racemization events. Additional embodiments and details are provided below.
  • Alkyl means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. C 1 -C 6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
  • alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
  • Alkoxyalkyl means a moiety of the formula R a —O—R b —, where R a is alkyl and R b is alkylene as defined herein.
  • exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.
  • Alkoxyalkoxy means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
  • Alkylcarbonyl means a moiety of the formula —C(O)—R, wherein R is alkyl as defined herein.
  • Alkoxycarbonyl means a group of the formula —C(O)—R wherein R is alkoxy as defined herein.
  • Alkylcarbonylamino means a group of the formula —R—C(O)—NR′— wherein R is alkyl and R′ is hydrogen or alkyl.
  • Alkylcarbonylalkyl means a group of the formula —R—C(O)—R′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Alkoxyalkylcarbonyl means a moiety of the formula —C(O)—R—R′, wherein R is alkylene and R′ is alkoxy as defined herein.
  • Alkoxycarbonylalkyl means a group of the formula —R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
  • Alkoxycarbonylamino means a moiety of the formula R—C(O)—NR′—, wherein R is alkoxy and R′ is hydrogen or alkyl as defined herein.
  • Alkoxycarbonylaminoalkyl means a moiety of the formula R—C(O)—NR′—R′′—, wherein R is alkoxy, R′ is hydrogen or alkyl, and R′′ is alkylene as defined herein.
  • Alkoxycarbonylalkoxy means a group of the formula —O—R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
  • Haldroxycarbonylalkoxy means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.
  • Alkylaminocarbonylalkoxy means a group of the formula —O—R—C(O)—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Dialkylaminocarbonylalkoxy means a group of the formula —O—R—C(O)—NR′R′′ wherein R is alkylene and R′ and R′′ are alkyl as defined herein.
  • Alkylaminoalkoxy means a group of the formula —O—R—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Dialkylaminoalkoxy means a group of the formula —O—R—NR′R′ wherein R is alkylene and R′ and R′′ are alkyl as defined herein.
  • Alkylsulfonyl means a moiety of the formula —SO 2 —R, wherein R is alkyl as defined herein.
  • Alkylsulfonylalkyl means a moiety of the formula —R′—SO 2 —R′′ where R′ is alkylene and R′′ is alkyl as defined herein.
  • Alkylsulfonylalkoxy means a group of the formula —O—R—SO 2 —R′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Amino means a moiety of the formula —NRR′ wherein R and R′ each independently is hydrogen or alkyl as defined herein. “Amino” also includes “alkylamino” (where one of R and R′ is alkyl and the other is hydrogen) and “dialkylamino” (where R and R′ are both alkyl.
  • Aminocarbonyl means a group of the formula —C(O)—R wherein R is amino as defined herein.
  • N-hydroxy-aminocarbonyl means a group of the formula —C(O)—NR—OH wherein R is hydrogen or alkyl as defined herein.
  • N-alkoxy-aminocarbonyl means a group of the formula —C(O)—NR—R′ wherein R is hydrogen or alkyl and R′ is alkoxy as defined herein.
  • Aminocarbonylaminoalkyl means a group of the formula R2N—C(O)—NR′—R′′— wherein each R is independently hydrogen or alkyl, R′ is hydrogen or alkyl, and R′′ is alkylene as defined herein.
  • N-alkyl-aminocarbonyl means a group of the formula —C(O)—NH—R wherein R is alkyl as defined herein.
  • N-hydroxy-N-alkylaminocarbonyl means a group of the formula —C(O)—NRR′ wherein R is alkyl as defined herein and R′ is hydroxy.
  • N-alkoxy-N-alkylaminocarbonyl means a group of the formula —C(O)—NRR′ wherein R is alkyl and R′ is alkoxy as defined herein.
  • N,N-di-C 1-6 alkyl-aminocarbonyl means a group of the formula —C(O)—NRR′ wherein R and R′ are alkyl as defined herein.
  • Aminosulfonyl means a group of the formula —SO 2 —NH 2 .
  • N-alkylaminosulfonyl means a group of the formula —SO 2 —NHR wherein R is alkyl as defined herein.
  • N,N-dialkylaminosulfonyl means a group of the formula —SO 2 —NRR′ wherein R and R′ are alkyl as defined herein.
  • Alkylsulfonylamino means a group of the formula —NR′—SO 2 —R wherein Rid alkyl and R′ is hydrogen or alkyl as defined herein.
  • N-(alkylsulfonyl)-aminoalkyl means a group of the formula —R—NH—SO 2 -R′ wherein R is alkylene and R′ is alkyl as defined herein.
  • N-(Alkylsulfonyl)aminocarbonyl means a group of the formula —C(O)—NH—SO 2 —R wherein R is alkyl as defined herein.
  • N-(Alkylsulfonyl)-N-alkylaminocarbonyl means a group of the formula —C(O)—NR—SO 2 —R′ wherein R and R′ are alkyl as defined herein.
  • N-Alkoxyalkyl-aminocarbonyl means a group of the formula —C(O)—NR—R′—OR′′ wherein R is hydrogen or alkyl, R′ is alkylene, and R′′ is alkyl as defined herein.
  • N-Hydroxyalkyl-aminocarbonyl means a group of the formula —C(O)—NR—R′—OH′′ wherein R is hydrogen or alkyl and R′ is alkylene as defined herein.
  • Alkoxyamino means a moiety of the formula —NR—OR′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.
  • Alkylsulfanyl means a moiety of the formula —SR wherein R is alkyl as defined herein.
  • Aminoalkyl means a group —R—R′ wherein R′ is amino and R is alkylene as defined herein.
  • Aminoalkyl includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide “alkylaminoalkyl” and “dialkylaminoalkyl” respectively.
  • Alkylaminoalkyl includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like.
  • Dialkylaminoalkyl includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.
  • Aminoalkoxy means a group —OR—R′ wherein R′ is amino and R is alkylene as defined herein.
  • Alkylsulfonylamido means a moiety of the formula —NR′SO 2 -R wherein R is alkyl and R′ is hydrogen or alkyl.
  • Aminocarbonyloxyalkyl or “carbamylalkyl” means a group of the formula —R—O—C(O)—NR′R′′ wherein R is alkylene and R′, R′′ each independently is hydrogen or alkyl as defined herein.
  • Alkynylalkoxy means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkynyl as defined herein.
  • Aryl means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring.
  • the aryl group can be optionally substituted as defined herein.
  • aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxy
  • Arylsulfonyl means a group of the formula —SO 2 —R wherein R is aryl as defined herein.
  • Aryloxy means a group of the formula —O—R wherein R is aryl as defined herein.
  • Alkyloxy means a group of the formula —O—R—R′′ wherein R is alkylene and R′ is aryl as defined herein.
  • Carboxy or “hydroxycarbonyl”, which may be used interchangeably, means a group of the formula —C(O)—OH.
  • Cyanoalkyl means a moiety of the formula —R′—R′′, where R′ is alkylene as defined herein and R′′ is cyano or nitrile.
  • Cycloalkyl means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino.
  • cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
  • Cycloalkenyl means a cycloalkyl as defined herein that includes at least one double bond or unsaturation.
  • Exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.
  • Cycloalkylalkyl means a moiety of the formula —R′—R′′, where R′ is alkylene and R′′ is cycloalkyl as defined herein.
  • Cycloalkylalkoxy means a group of the formula —O—R—R′ wherein R is alkylene and R′ is cycloalkyl as defined herein.
  • Cycloalkylcarbonyl means a moiety of the formula —C(O)—R, wherein R is cycloalkyl as defined herein.
  • C 3-6 cycloalkyl-C 1-6 alkyl-carbonyl means a moiety of the formula —C(O)—R, wherein R is cycloalkylalkyl as defined herein.
  • Cyanoalkylcarbonyl means a moiety of the formula —C(O)—R—R′, wherein R is alkylene as defined herein and R′ is cyano or nitrile.
  • N-Cyano-aminocarbonyl means a moiety of the formula —C(O)—NHR, wherein R is cyano or nitrile.
  • N-Cyano-N-alkyl-aminocarbonyl means a moiety of the formula —C(O)—NRR′—R, wherein R′ is alkyl as defined herein and R is cyano or nitrile.
  • Cycloalkylsulfonyl means a group of the formula —SO 2 —R wherein R is cycloalkyl as defined herein.
  • Cycloalkylalkylsulfonyl means a group of the formula —SO 2 —R wherein R is cycloalkylalkyl as defined herein.
  • Forml means a moiety of the formula —C(O)—H.
  • Heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • the heteroaryl ring may be optionally substituted as defined herein.
  • heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl
  • Heteroarylalkyl or “heteroaralkyl” means a group of the formula -R-R′ wherein R is alkylene and R′ is heteroaryl as defined herein.
  • Heteroarylsulfonyl means a group of the formula —SO 2 -R wherein R is heteroaryl as defined herein.
  • Heteroaryloxy means a group of the formula —O—R wherein R is heteroaryl as defined herein.
  • Heteroarylcarbonyl means a group of the formula —C(O)—R wherein R is heteroaryl as defined herein.
  • Heteroaralkyloxy means a group of the formula —O—R—R′′ wherein R is alkylene and R′ is heteroaryl as defined herein.
  • halo refers to a substituent fluoro, chloro, bromo, or iodo.
  • Haloalkyl means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen.
  • exemplary haloalkyls include —CH 2 Cl, —CH 2 CF 3 , —CH 2 CCl 3 , perfluoroalkyl (e.g., —CF3), and the like.
  • Haloalkoxy means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein.
  • An exemplary haloalkoxy is difluoromethoxy.
  • Heterocycloamino means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
  • Heterocyclyl means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur).
  • the heterocyclyl ring may be optionally substituted as defined herein.
  • Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like.
  • Such heterocyclyl may be optionally substituted as defined herein.
  • Heterocyclylalkyl means a moiety of the formula —R—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
  • Heterocyclyloxy means a moiety of the formula —OR wherein R is heterocyclyl as defined herein.
  • Heterocyclylalkoxy means a moiety of the formula —OR—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
  • Haldroxyalkoxy means a moiety of the formula —OR wherein R is hydroxyalkyl as defined herein.
  • Haldroxyalkylamino means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is hydroxyalkyl as defined herein.
  • Haldroxyalkylaminoalkyl means a moiety of the formula —R—NR′—R′′ wherein R is alkylene, R′ is hydrogen or alkyl, and R′′ is hydroxyalkyl as defined herein.
  • Haldroxycarbonylalkyl or “carboxyalkyl” means a group of the formula —R—(CO)—OH where R is alkylene as defined herein.
  • Haldroxycarbonylalkoxy means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.
  • Haldroxyalkylcarbonyl means a moiety of the formula —C(O)—R—R′, wherein R is alkylene as defined herein and R′ is hydroxy.
  • Haldroxyalkyloxycarbonylalkyl or “hydroxyalkoxycarbonylalkyl” means a group of the formula —R—C(O)—O—R—OH wherein each R is alkylene and may be the same or different.
  • “Hydroxyalkyl” means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.
  • Hydrocycloalkyl means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
  • Oxo means a group of the formula ⁇ O (i.e., an oxygen with a double bond).
  • a 1-oxo-ethyl group is an acetyl group.
  • Alkoxy hydroxyalkyl and “hydroxy alkoxyalkyl”, which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy.
  • Alkoxy hydroxyalkyl and “hydroxy alkoxyalkyl” thus encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.
  • Rea or “ureido” means a group of the formula —NR′—C(O)—NR′′R′′′ wherein R′, R′′ and R′′′ each independently is hydrogen or alkyl.
  • “Carbamate” means a group of the formula —O—C(O)—NR′R′′ wherein R′ and R′′ each independently is hydrogen or alkyl.
  • Carboxy means a group of the formula —O—C(O)—OH.
  • “Sulfonamido” means a group of the formula —SO 2 -NR′R′′ wherein R′, R′′ and R′′′ each independently is hydrogen or alkyl.
  • Optionally substituted when used in association with an “aryl”, “phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” moiety means that such moiety may be unsubstituted (i.e., all open valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein.
  • leaving group means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions.
  • Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
  • Module means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
  • Disease and Disease state means any disease, condition, symptom, disorder or indication.
  • “Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tent-butanol, dioxane, pyridine, and the like.
  • the solvents used in the reactions of some embodiments are inert solvents.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
  • Protecting group means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of some embodiments rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants.
  • the terms “amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures.
  • Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.
  • Bn benzyloxycarbonyl
  • CBZ benzyloxycarbonyl
  • p-methoxybenzyloxycarbonyl p-nitrobenzyloxycarbonyl
  • tert-butoxycarbonyl BOC
  • Solidvates means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
  • Arthritis means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
  • Respiratory disorder refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
  • COPD chronic obstructive pulmonary disease
  • Subject means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • Treating” or “treatment” of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • treating when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
  • the disclosure provides and methods for making the ring portion of arylomycin, and hence methods for making arylomycin analogs, with unexpectedely improved yields and improved chiral purity.
  • the subject methods utilize the palladium catalyst chloro(crotyl)(tri-tert-butylphosphine)palladium(II), also known as “Pd162”, in a Suzuki coupling reaction to make the arylomycin ring in high overall yield.
  • Pd162 has the structure:
  • Pd162 is commercially available from Johnson Matthey Fine Chemicals and other sources, and may be prepared according to the procedure reported by DeAnglis et al., J. Org. Chem. Vol. 80, pp 6794-6813 (2015). Use of Pd162-based coupling in accordance with some embodiments results in yields of about 85% in an important step in the formation of the arylomycin ring.
  • Amide coupling reactions are utilized in many of the synthetic procedures described herein and the reagents involved can be used interchangeably in many instances.
  • Amide coupling as described herein may in many embodiments utilize carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride (EDC or EDCI).
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC or EDCI ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride
  • 1-Hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) may be used with carbodiimide based coupling reactions to mimize race
  • additional reagents that may be used for amide coupling, include (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP).
  • BOP Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
  • PyBOP Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
  • PyAOP 7-Azabenzotriazol-1-yloxy)tripyr
  • amide coupling reagents usable include O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), O-(N-Suc
  • R is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; cyano-C 1-6 alkyl; or nitro, wherein the amino and hydroxyl moieties each may optionally include a protecting group;
  • R 7 is: hydrogen; or C 1-4 alkyl
  • R 8 is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; or cyano-C 1-6 alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group;
  • R 9 is: C 1-4 alkyl; halo-C 1-4 alky; hydroxyl-C 1-4 alkyl; amino-C 1-4 alkyl, aminosulfonyl-C 1-4 alkyl; or C 1-4 alkoxy-C 1-4 alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group;
  • R 10 is: hydroxyl-C 1-4 alkyl; amino-C 1-4 alkyl; aminosulfonyl-C 1-4 alkyl; or C 1-4 alkoxy-C 1-4 alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group;
  • R a is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence, or two R groups may form a C 2-6 alkylene that, together with the atoms to which they are attached, may form a five- or six-membered ring;
  • X is a leaving group
  • Y is halogen (fluoro, chloro, bromo or iodo);
  • Pg 1 is an optional amine protecting group and may be the same or different in each occurrence;
  • Pg 2 is an optional hydroxyl protecting group and may be the same or different in each occurrence;
  • TG is a “tail group” and is defined further herein;
  • WG is a “warhead group” and is defined further herein.
  • step 1 of Scheme 1A synthesis of an intermediate halodophenol compound e is shown.
  • phenol aminoacid compound a undergoes halogenation to afford halophenol aminoacid compound b.
  • halogenation of step 1 may be carried out using Fl 2 , Cl 2 , Br 2 or I 2 in aqueous ammonia solution at reduced temperature. In many embodiments I 2 is used in this step.
  • an amine protecting group may be introduced to provide amine-protected halophenol aminoacid compound c.
  • the protecting groups in many embodiments can be a carboxybenzyl (cbz) group, with the reaction of step 2 achieved using carboxybenzyl chloride with compound b under basic aqueous conditions.
  • a ring formation is carried out in step 3 by reaction of compound c with trioxane to afford halophenol oxooxazoldine compound d.
  • the reaction of step 3 may occur in polar aprotic solvent such as THF or methyl-THF and in the presence of tosylic acid.
  • step 4 A reduction reaction is then carried out in step 4 to give N-methyl aminoacid intermediate compound e.
  • the reaction of step 4 may be done using a hydrosilane reagent such as triethylsilane under acidic conditions using trifluoroacetic acid in polar aprotic solvent such as dichloromethane.
  • Compound e may then be used as shown below in Scheme 1C or 1D.
  • Scheme 1B illustrates the syntehsise of boronate intermediate compound j, wherein Y, R, R 1 , R 2 , R 3 , R 4 ,R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as defined herein.
  • step 1 of Scheme 1B phenol aminoacid f is halogenated to give halophenol aminoacid compound g.
  • this reaction may utilize Fl 2 , Cl 2 , Br 2 or I 2 as an halogenation reagent, and the reaction may be carried out in aqueous ammonia solution at reduced temperature.
  • step 2 the carboxylate group of compound g is optionally protected via esterification, to afford the corresponding ester compound h.
  • This esterification may be achieved using methanol (to form methyl ester) or other lower alcohol as solvent and in the presence of acid or acid chloride.
  • step 3 An amide coupling is carried out in step 3 wherein optionally protected amino acid compound i is reacted with compound h to provide dipeptide compound
  • amide coupling reagents and conditions may be used in this step as noted above.
  • the amide coupling of step 3 may be achieved utilizing 6-Chloro-2,4-dimethoxy-s-triazine (CDMT) in the presence of N-methyl morpholine in polar aprotic solvent such as dichloromethane.
  • CDMT 6-Chloro-2,4-dimethoxy-s-triazine
  • the protected amino acid I may be Boc-protected alanine such that R 8 is (s)-methyl.
  • a hydroxyl protecting group is optionally introduced onto compound j to afford O-protected compound k.
  • the protecting group may be benzyl and is provided by reaction of compound j with benzyl halide in polar aprotic solvent such as acetone, and optionally in the presence of a mild base such as potassium carbonate.
  • a boronate ester is formed in step 5 by treatment of compound k with a boronating agen (not shown) t to yield boronate compound l.
  • the boronating agent may be pinacolborane or bis(pinacolato)diboron (4,4,5,5-Tetramethyl-1,3,2-dioxaborolane). This reaction is carried out in the presence of a palladium catalyst such as Pd(dppf)Cl 2 in polar aprotic solvent such as DMSO.
  • the boronate ester may optionally be hydrolyzed (not shown) to the corresponding boronic acid. Such hydrolysis may be effected using acid such as HCl in the presence of sodium periodate in polar aprotic solvent such as THF or methyl-THF.
  • step 6 top remove the amine protecting group from compound l to give compound m.
  • the deprotection reaction may utilize HCl or other acid in methanol solvent.
  • Compound m may be then be used as described in Scheme 1C and 1D below.
  • Scheme 1C illustrates the synthesis of arylomycin ring compound o, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as defined herein.
  • step 1 of Scheme 1C the phenyl halo N-methyl aminoacid compound e is reacted with boronate dipeptide compound m from Scheme 1B, via an amide coupling reaction, to give tripeptide compound n.
  • amide coupling reagents and conditions may be used in this step, and in one embodiment the reaction is carried out using isobutyl chloroformate (IBCF) in the presence of N-methyl morpholine, in polar aprotic solvent such as DMF, THF, or a mixture thereof.
  • IBCF isobutyl chloroformate
  • step 2 a Suzuki-type coupling reaction is carried out to effect a ring closure in compound n, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (“Pd162”), and thus afford arylomycin ring compound o in accordance with some embodiments.
  • the reaction of step 2 may be done in aqueous acetonitrile and in the presence of mild base such as potassium bicarbonate.
  • step 2 occurs in high yield, and in many embodiments a yield of at least 60-70% under kilogram scale conditions, and in some embodiments 75% is achieved, and certain embodiments at least 80%, and in some embodiments 85%, which are substantially and unexpectedly better yields than has previously been achieved utilizing several different palladium catalysts under different conditions.
  • Previously reported synthetic yields for arylomycin ring formation are substantially lower than are achieved by some embodiments.
  • Dufour et al., Chem. Eur. J. 2010, 16, 10523-10534 reported yields ranging from O-54% using multiple different Pd catalysts, and such yields have not been reproducible beyond benchtop scale reactions.
  • 129, 15830-15838 report yields of only 19-40% utilizing various different Pd catalysts and different solvent conditions and, again, the reported yields are not repeatable in larger scale reactions.
  • Some embodiments also unexpected provide chiral purity of >99% de.
  • Scheme 1D demonstrates the synthesis of arylomycin ring compound o via an alternate route, wherein Y, R, R 1 , R 2 , R 3 , R 4 ,R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as defined herein.
  • step 1 a Suzuki-type coupling reaction is used with compound m from Scheme 1B and compound e from Scheme 1A, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (“Pd162”), to afford bispehnol compound x.
  • the reaction of step 1 may be carried out in aqueous THF and in the presence of potassium phosphate.
  • This reaction occurs in high yield, and in many embodiments a yield of at least 75% is achieved, and certain embodiments at least 80%, and in some embodiments 85%, which are substantially and unexpectedly better yields than has previously been achieved utilizing several different palladium catalysts under different conditions.
  • 129, 15830-15838 reports a yield of 36% using PdCl2(dppf) in DMOS.
  • Some embodiments also unexpected provide chiral purity of >99% de.
  • step 2 compound x undergoes cyclization via amide coupling to afford arylomycin ring compound o in accordance with some embodiments.
  • the amide compling in certain embodiments may be done in the presence of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N-methyl morpholine in polar aprotic solvent such as DMF.
  • Scheme 1E demonstrates the synthesis of arylomycin analog compounds w from ring compound o, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Pg 1 and Pg 2 are as defined herein.
  • reagent p is an amino-C 1-4 alkyl halide wherein the amino includes a protecting group such as Boc.
  • the alkylation reaction may be carried out in dimethylacetamide or other polar aprotic solvent in the presence of potassium phosphate. This step may be omitted such that the phenolic hydroxyl groups of compound o are un-alkylated.
  • protecting group Pg 2 may be removed prior to step 1 and both phenolic hydroxyl groups may be reacted with agent p.
  • step 2 O-deprotection and/or N-deprotection are optionally carried out to remove groups Pg 2 and/or Pg 1 , to provide compound r.
  • Pg 1 and Pg 2 are carbobenzoxy (Cbz) and benzyl (Bn) respectively
  • both protecting groups may be removed in a single reaction via reductive debenzylation in the presence of hydrogen gas and Pd/C in dimethylactemide or lake polar aprotic solvent.
  • step 3 an amide coupling reaction is carried out by reaction of protected amino acids with compound r to yield compound t.
  • the amide coupling of step 3 may utilize O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in the presence of diisopropyl ethylamine (DIPEA) in polar aprotic solvent such as THF or methyl-THF.
  • DIPEA diisopropyl ethylamine
  • amino acid s may be lysine, diaminobutyric acid, or like amino acid wherein R 10 is an aminoalkyl group (which may be suitably protected).
  • R 10 is an aminoalkyl group (which may be suitably protected).
  • Pg 1 of amino acid s may be 9-fluorenyl-methyloxycarbonyl (Fmoc), while R 10 is —CH 2 —CH 2 —NHBoc.
  • Step 3 may be repeated one or more times to couple additional amino acids s onto compound t.
  • step 3 would occur three times: first using glycine, followed by alanine, and last by N-methylserine, to provide the residues found in native arylomycin.
  • step 4 the protecting group Pg 1 (that was introduced in step 3 on amino acid s) is removed, and amide coupling is carried out by reacting the (deprotected) compound t with “tail group” carboxylate reagent u.
  • deprotection may occur using tetrabutylammonium chloride (TBAF) in polar aprotic solvent such as THF or methyl-THF.
  • TBAF tetrabutylammonium chloride
  • polar aprotic solvent such as THF or methyl-THF.
  • the amide coupling of step 4 may be effected using ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxy-7-azabenzotriazole (HOAt). Further details for tail group reagent u are provided below.
  • an ester hydrolysis occurs to remove the carboxy protecting group R from compound v, and the resulting carboxylate compound (not shown) is reacted with amine reagent w to introduce a “warhead” group WG and provide compound x.
  • the ester hydrolysis may utilize aqueous lithium hydroxide or other alkalai metal hydroxide in a water miscible polar solvent such as THF.
  • the amide coupling may use O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in the presence of DIPEA in polar aprotic solvent such as THF or methyl-THF. Further details for warhead group reagent w are provided below.
  • the tail group TG is in many embodiments a hydrophobic group or a group including a hydrophobic portion.
  • the group TG would be an isoundecyl (C 11 ) group, such that reagent u is isododecanoic acid.
  • X 1 and X 2 each independently is N or C;
  • n and n each independently is 0, 1 or 2;
  • R b is:
  • R c and R d each independently is: C 1-4 alkyl, halo-C 1-4 alkyl or halo.
  • the warhead group reagent w may be glycine nitrile (H 2 N—CH 2 —CN) so that the group WG is —CH 2 CN.
  • WG may be heteroaryl, amido, epoxy, or other group.
  • some embodiments provide a method for making an arylomycin ring of formula o
  • Y is halogen (fluoro, chloro, bromo or iodo);
  • R is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; cyano-C 1-6 alkyl; or nitro, wherein the amino and hydroxyl moieties may optionally include a protecting group;
  • R 7 is: hydrogen; or C 1-4 alkyl
  • R 8 is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; or cyano-C 1-6 alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group;
  • R a is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence, or two R groups may form a C 2-6 alkylene that, together with the atoms to which they are attached, may form a five- or six-membered ring;
  • Pg 1 is an optional amine protecting group
  • Pg 2 is an optional hydroxyl protecting group
  • R, R 1 , R 2 , R 3 , R 4 ,R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as defined herein;
  • the subject methods may further comprise:
  • the subject methods may further comprise:
  • the reagent u is a compound of formula z
  • n and n each independently is 0, 1 or 2;
  • R b is:
  • R b and R c each independently is: C 1-4 alkyl, halo-C 1-4 alkyl or halo.
  • the reagent w is cyano-C 1-4 alkylamino, such as glycine nitrile or H 2 N—CH 2 —CN. so that the group WG is cyano-C 1-4 alkyl such as —CH 2 CN. In other embodiments WG may be heteroaryl, amido, epoxy, or other group. In such embodiments, the compound of formula x may be of formula A
  • the rxn mixture was concentrated at 45 ⁇ 55° C. (water batch 55 ⁇ 60° C.) to remove most of 1,4-dioxane ( ⁇ 100 kg 1,4-dioxane & water were collected). The residue was cooled to 20 ⁇ 30° C. and aq. solution of LiOH—H 2 O (51 kg, 1215 mol, 2.5 equiv. in 2140 kg of water, 15 w) was added over 1 h. The mixture was stirred for 1 h at 20 ⁇ 30° C.
  • the rxn mixture was stirred at 70 ⁇ 75° C. for another 1 hr. (a sample was taken for HPLC analysis: A3 ⁇ 5 A %).
  • the rxn mixture was cooled to 25 ⁇ 30° C. and 2700 kg (16 w) of water (15 ⁇ 20° C.) was added over 3 hrs. (mild exothermic. IT rose to 28° C. from 20° C.). Stopped agitation and allowed separation of phases.
  • the aqueous phase was extracted with EtOAc (800 kg, 5 w).
  • the organic phases were combined and washed with aq. Na 2 CO 3 which was made by dissolving 29 kg Na 2 CO 3 in1600 kg of water (the pH of the resulting aqueous was ⁇ 9).
  • the phases were separated and the organic phase was washed with brine (50 kg NaCl in 600 kg water). The organic phase was dried over anhydrous Na 2 SO 4 (50 kg) for 1 hr. before filtration.
  • the filtrate (combined with the filtrate from the batch with 30.6 kg of A3) was concentrated at 40 ⁇ 45° C. (jacket temperature 45 ⁇ 50° C.) under vacuum to 300 ⁇ 350 kg stage. Petroleum ether (400 kg, 2 w) was added and the mixture was concentrated under vacuum at 40 ⁇ 45° C. again to 350 ⁇ 400 kg stage again (a large amount of solid was precipitated out). Petroleum ether (780 kg, 4 w) was added. The suspension was cooled to 15 ⁇ 25° C. and stirred for 1 hr.
  • Na 2 CO 3 solution (140 kg of Na 2 CO 3 dissolved in 1260 kg water) was added to adjust the pH of the DCM solution to ⁇ 9.
  • the phases were separated.
  • DCM 700 kg, 5 w
  • the pH of the mixture was adjusted to ⁇ 2 with ⁇ 100 kg 30% HCl.
  • the mixture was then stirred at 15 ⁇ 25° C. for ⁇ 2 hrs. before filtration.
  • the cake was rinsed with water (140 kg, 1 w) and slurried in DCM (650 kg, 4.5 w) at 15 ⁇ 25° C. for ⁇ 1 hr.
  • the slurry was centrifuged and rinsed with DCM (140 kg, 1 w).
  • the wet cake was dried at 35 ⁇ 45° C.
  • the pH of the mixture was continuously adjusted using aqueous HCl (18 w %) to 7.4 over ⁇ 3 hrs. and 6.6 over ⁇ 1 hr., and stirred for 1 hr. at each pH stage.
  • the resultant was stirred at 20 ⁇ 30° C. for 2 h (a total of ⁇ 1200 kg of 18 w % aq. HCl was used for crystallization).
  • the slurry was centrifuged.
  • the wet cake was washed twice with water (230 kg, 1.6 w, each) and then twice with acetone (230 kg, 1.6 w, each).
  • the solid was dried under vacuum at 50-60° C. for ⁇ 48 hrs. to afford 156.6 kg of A7 with 96 A % purity & 2.5 w % water content as a light brown solid in 62.6% yield (uncorrected; subtract 0.25 kg of A7 seed).
  • Acetone 45 kg, 0.6 w was added and the mixture was concentrated under vacuum at 35 ⁇ 45° C. to ⁇ 100 kg of residue again. This repeated one more time to purge DCM. More acetone (240 kg, 3.4 w) was added and the solution was cooled to 15 ⁇ 25° C. The A10/acetone solution (330 kg) was used directly for next step.
  • the combined filtrate was concentrated under vacuum at 30 ⁇ 50° C. to ⁇ 300 kg of residue and petroleum ether (800 kg, 5.3 w of A8-HCl) was added over 20 min. The mixture was cooled to 0 ⁇ 10° C. and stirred for 1 h. The slurry was filtered and the cake was rinsed with DCM/petroleum ether (45 kg/90 kg). The wet cake ( ⁇ 240 kg) was dissolved in DCM (500 kg, 3.3 w of A8-HCl) at 20 ⁇ 30° C. Petroleum ether (500 kg, 3.3 w of A8-HCl) was added dropwise over 40 min. The slurry was cooled to 0 ⁇ 5° C. and stirred for 1 h.
  • the slurry was filtered.
  • the wet cake was slurried in DCM/petroleum ether (250 kg/500 kg) at 20 ⁇ 30° C. for 0.5 h.
  • the slurry was filtered and the cake was rinsed with DCM/petroleum ether (45 kg/90 kg).
  • the wet cake was dried under vacuum at 20 ⁇ 40° C. (jacket temperature, 40 ⁇ 45° C.) for ⁇ 30 hrs.
  • About 134.6 kg of A11 was obtained as an off-white solid with 96.6 A % purity, >99% de & 96.1 w % (by qNMR) in 54.9% yield (uncorrected) over 2 steps from 150.6 kg of A8-HCl.
  • the reaction mixture was cooled to 25 ⁇ 30° C. and quenched into a mixture of water (610 kg, 10 w) & MTBE (670 kg, 11 w). The mixture was filtered through a diatomite pad (25 kg). The phases (the filtrate) were separated and the aqueous was extracted with MTBE (115 kg, 1.9 w). The combined MTBE extracts were dried over anhydrous Na 2 SO 4 (50 kg) for 1 hr. before filtration. The cake was rinsed with MTBE (30 kg, 0.5 w) and the combined filtrate was concentrated under vacuum at 25 ⁇ 40° C. to afford 407 kg of MTBE solution which was used for next step directly.
  • ACN 190 kg, 1.6 w of A11
  • ACN 190 kg, 1.6 w of A11
  • ACN 920 kg, 7,5 w of A11
  • the mixture was cooled to 10 ⁇ 20° C. and stirred for 1 h.
  • the slurry was filtered and the cake was rinsed with ACN (60 kg).
  • the wet product was dried at 30 ⁇ 45° C. under vacuum for 24 hrs.
  • a HCl aqueous solution (4 w %, 7.4 kg, 0.105 eq.) was added slowly at 10 ⁇ 15° C. over 1.5 hrs. The mixture was warmed to 15 ⁇ 20° C. and stirred for 6 hrs (slightly exothermic). Upon the rxn completion, the mixture was filtered and the solid was rinsed with MeTHF (8 kg, 0.2 w). Aqueous NaHSO 3 solution (16 kg NaHSO 3 in 48 kg water) was added slowly to above combined filtrate below 15° C. over ⁇ 0.5 hrs.(exothermic). The phases were separated and the aqueous was extracted with MeTHF (28 kg, 0.7 w).
  • the MeTHF extracts were combined and washed with brine (16 kg NaCl in 64 kg water). The organic phase was dried over anhydrous Na 2 SO 4 (120 kg) for 2 hrs. before filtration. The cake was rinsed with MeTHF (30 kg, 0.75 w). The MeTHF solution obtained above was added slowly to TBME (460 kg, 11.5 w) over 2 hrs. with stirring at 10 ⁇ 15° C. (solid was precipitated out upon the completion of adding MeTHF solution). The slurry was stirred at 10 ⁇ 15° C. for additional 1 hr. before filtration. The wet product was dried at 5 ⁇ 15° C. under vacuum for ⁇ 72 hrs. to give ⁇ 26 kg of A14-HCl as a light brown solid with 96 A % purity & 90 w % (by qNMR) in 77.2% yield (uncorrected).
  • the rxn mixture was added slowly to the mixture of aqueous Na 2 CO 3 & EA below 0° C. over 1 hr. Then, the resulting mixture was stirred for 20 min. before filtration. The phases (the filtrate) were separated. The organic phase was washed with aq NH 4 Cl (64 kg NH 4 Cl dissolve in 260 kgs of water), followed by brine for 3 times (50 kgs of NaCl dissolved in 250 kg water, each). The organic phase was dried over anhydrous Na 2 SO 4 (30 kg). Filtered and the cake was rinsed with EA (30 kg). The Filtrate was concentrated under vacuum at 30 ⁇ 45° C. to ⁇ 50 kgs residue (2 ⁇ 2.5 w of A14-HCl).
  • EtOH (20 kg) was added and the mixture was distilled under vacuum at 30 ⁇ 45° C. to ⁇ 50 kg again (2 ⁇ 2.5 w of A14-HCl). This operation was repeated twice (each with 20 kg EtOH) to remove EtOAc (GC: ⁇ 5 A % of EA in the residue) (product began to be precipitated out during the 3 rd time concentration). More EtOH (51.3 kg, 2 w of A14-HCl) was added. The mixture was heated to 60 ⁇ 65° C. and stirred for 3 hrs. (some solids was dissolved). Then, n-heptane (74 kg, 2.9 w of A14-HCl) was added slowly over 1 hr.
  • Acetonitrile (7.5 L, 25 v) and DI water (7.5 L, 25 v) (acetonitrile & DI water evacuated and backfilled with N 2 10 min ⁇ 3 times respectively in advance) were added under N 2 .
  • the vessel containing the rxn mixture was again evacuated and backfilled with N 2 (15 min).
  • the mixture was heated to 65° C. over ⁇ 1 h and stirred for additional 1.5 h or until the completion of the reaction (A15: ⁇ 1.0 A % on HPLC).
  • the rxn mixture was cooled to ambient temperature and diluted with DCM (27 v, 8 L). The phases were separated and the aqueous was extracted with DCM ( ⁇ 8 v, 2 L).
  • Scheme 2D illustrates an alternate route to synthesis of Methyl(4S,7S,10S)-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methyl)amino)-16-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A16)
  • the rxn mixture was diluted with EtOAc (45 L, 25 v related to A15) & 30 L of ID water. The phases were separated and the organic phase was washed with 10% brine (9 L ⁇ 3, standing for ⁇ 1 h for each time). The filtrate and wash were combined and dried with 1.5 kg of anhydrous Na 2 SO 4 for 30 min with stirring. Filtered and the cake was washed with EtOAc (2 L), the combined filtrate was concentrated under vacuum at 45° C. for ⁇ 3 h to afford an oil. Slurrying the oil in MeOH/EA/MTBE (3.75 L/1.5 L/3 L) at 10 ⁇ 20° C. for 20 h afforded a white solid.
  • the resulting suspension was cooled with ice water to ⁇ 20° C. in a period of ⁇ 40 mins.
  • the suspension was filtered and the cake was washed with 200 mL of n-heptane.
  • the wet solid was dried under vacuum at 50° C. for 4 h to afford 115 g of A20 as an off-white solid with 98.4 A % LC purity (major impurity @15.5 min, 0.85 A %) in 80% yield (uncorrected).
  • the reaction was stirred at rt for 4 h.
  • IPAc 38 mL, 1.4 V
  • 10% aq K 2 HPO 4 192 mL, 7 V
  • the organic layer was treated with 10 wt % aq K 2 HPO 4 (190 mL, 7 V).
  • the organic layer was then treated with 20 wt % citric acid (275 mL, 10 V), DMA (27.5 mL, 1 V) and heptane (137.5 mL, 5 V) in this order while stirring.
  • the aqueous layer was then treated with heptane (137.5 mL, 5 V).

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